Methods and compositions related to targeting monoacylglycerol lipase

Abstract

This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2-Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The subject patent application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 199,286 (filed Nov. 14, 2008). The full disclosures of the priority application are incorporated herein by reference in their entirety and for all purposes.STATEMENT CONCERNING GOVERNMENT SUPPORT[0002]This invention was made in part with government support under Grant Nos. R01-DA017259 and R01-DA025285 from the National Institutes of Health. The U.S. Government may therefore have certain rights in this invention.COPYRIGHT NOTIFICATION[0003]Pursuant to 37 C.F.R. §1.71(e), Applicants note that a portion of this disclosure contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.FIELD OF...

AI Technical Summary

Benefits of technology

[0012]In still another aspect, the invention provides methods for identifying MAGL inhibitor compounds with improved properties. The methods entail (a) synthesizing one or more structural analogs of a MAGL selective inhibitor disclosed herein (e.g., JZL184); (b) performing a functional assay on the analogs to identify an analog that has an improved biological or pharmaceutical property relative to that of the MAGL selective inhibitor. Any of the compounds encompassed by formula I can serve as the lead compound for synthesis of structural analogs. In some preferred embodiments, compound JZL184 is used. In these screening methods, the improved biological or pharmaceutical property to be identified in the analogs can be, e.g., an enhanced inhibitory activity for MAGL or an increased selectivity for MAGL over other brain serine hydrolases.

[0013]In another aspect, the invention provides methods for inhibiting growth of tumor cells, especially aggressive tumor cells. The methods entail contacting the tumor cells with a therapeutically effective amount of a compound that specifically inhibits monoacylglycerol lipase (MAGL). In some embodiments, the methods are directed to inhibiting growth of a tumor that is present in a subject. The subject can be one who is diagnosed to have a cancer. The subject can also be one who is predisposed to or at risk of developing a cancer. The methods can be employed to inhibit growth of any tumor cells including cells of solid tumor and leukemia. In some embodiments, the methods are used to inhibit growth of a breast tumor cell, an ovarian tumor cell, a melanoma cell, a lung tumor cell or a brain tumor cell.

Problems solved by technology

However, none of these previous studies have specifically examined the role that MAGL plays in hydrolyzing 2-AG in vivo.

Tumors and cancers are common diseases or conditions that threaten many people's life and health.

Uninhibited growth of aggressive tumor cells often results in the formation of malignant tumors (cancer).

There are still no effective medicines or treatments which can radically cure cancers.

However, most available treatments can only relieve the patients' symptom and physical sign but can not cure the disease, and each of the treatments usually has its disadvantages including side effects.

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